Inhibition Of Renal Prostaglandin Synthesis Research Articles

Hyperpotassemia and Bradycardia in a Bedridden Elderly Woman with Selective Hypoaldosteronism Associated with Low Renin Activity

A bedridden 85-year-old woman had hyperpotassemia (7.7 mEq/L) and bradycardia (30/min). Endocrinologic findings revealed a decrease in the renin-aldosterone system and normal adrenoglucocorticoid function. The results were consistent with the abnormalities seen in selective hypoaldosteronism with low renin activity. In addition, 9 of 11 patients, selected randomly from 72 bedridden elderly patients with normal serum sodium and potassium levels in our hospital, had diminished plasma renin activity (PRA) and plasma aldosterone concentration (PAC). The present patient was prescribed nonsteroidal anti-inflammatory drug (NSAID). NSAID reduces renal potassium excretion through the inhibition of renal prostaglandin synthesis. Therefore, the use of NSAID in bedridden elderly patients might intensify the underlying asymptomatic hypoaldosteronism and cause life-threatening hyperpotassemia.

Electrolyte and Acid-Base Disturbances Associated with Non-Steroidal Anti-Inflammatory Drugs

Inhibition of renal prostaglandin synthesis by non-steroidal anti-inflammatory drugs (NSAIDs) causes various electrolyte and acid-base disturbances including sodium retention (edema, hypertension), hyponatremia, hyperkalemia, and decreased renal function. Decreased sodium excretion can result in weight gain, peripheral edema, attenuation of the effects of antihypertensive agents, and rarely aggravation of congestive heart failure. Although rare, NSAIDs can cause hyponatremia by reducing renal free water clearance. Hyperkalemia could occur to a degree sufficient to cause cardiac arrhythmias. Renal function can decline sufficiently enough to cause acute renal failure. NSAIDs associated electrolyte and acid-base disturbances are not uncommon in some clinical situations. Adverse renal effects of NSAIDs are generally associated with prostaglandin dependent states such as volume-contracted states, low cardiac output, or other conditions that tend to compromise renal perfusion. All NSAIDs seem to share these adverse effects. In view of many NSAIDs users' susceptibility to renal adverse effects due to their underlying disease or condition, physicians should be cautious in prescribing NSAIDs to susceptible patients.

Investigation on urinary proteins and renal mRNA expression in canine renal papillary necrosis induced by nefiracetam

The occurrence of renal papillary necrosis (RPN), seen only in dogs after repeated oral administration of nefiracetam, a neurotransmission enhancer, at a relatively high dose, is because of inhibition of renal prostaglandin synthesis by the nefiracetam metabolite M-18. In this study, analyses of urinary proteins and renal mRNA expression were performed to investigate the possible existence of a specific protein expressing the characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins from male dogs given nefiracetam at 300 mg kg(-1) day(-1) over weeks 5-11, a protein of approximately 40 kDa, which was not seen in control urine, and protein of approximately 30 kDa emerged as distinct bands. Subsequently, clusterin precursor was identified in the former band and tissue kallikrein precursor in the latter by LC-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS). By quantitative real-time RT-PCR analysis with renal morphological aspects, individual findings showed that renal clusterin mRNA was increased in dogs with severe renal injury, and renal tissue kallikrein also increased, presumably related to hemodynamics. These results demonstrate that changes in renal clusterin mRNA may reflect the progression or severity of RPN, whereas upregulation of tissue kallikrein mRNA may subsequently play a compensating role in the prevention of RPN.

Renal function in a rat model of analgesic nephropathy: effect of chloroquine.

The antimalaria drug chloroquine is often taken against a background of analgesic nephropathy caused by nonsteroidal anti-inflammatory drugs such as paracetamol (acetaminophen). Chloroquine has marked effects on the normal kidney and stimulates an increase in plasma vasopressin via nitric oxide. The aim of this study was to determine the renal action of chloroquine in a model of analgesic nephropathy. Sprague-Dawley rats (n = 6-8/group) were treated with paracetamol (500 mg kg(-1) day(-1)) for 30 days in drinking water to induce analgesic nephropathy; control rats received normal tap water. Under intraval anesthesia (100 mg kg(-1)) rats were infused with 2.5% dextrose for 3 h to equilibrate and after a control hour they received either vehicle, chloroquine (0.04 mg h(-1)), N(omega)-nitro-L-arginine methyl ester (L-NAME, nitric-oxide synthase inhibitor, 60 micro g kg(-1) h(-1)) or combined chloroquine and L-NAME over the next hour. Plasma was collected from a parallel group of animals for vasopressin radioimmunoassay. Long-term paracetamol treatment resulted in a decrease in glomerular filtration rate (p < 0.05), sodium excretion (p < 0.001), and urine osmolality (p < 0.001), but no change in urine flow rate compared with untreated animals. Chloroquine administration in paracetamol treated rats induced a significant reduction (p < 0.05) in urine flow rate and a significant increase in plasma vasopressin (p < 0.001). These effects were blocked by coadministration of L-NAME and thus seem to be mediated by a pathway involving nitric oxide. However, these responses contrast with the chloroquine-induced diuresis previously observed in untreated rats, possibly reflecting paracetamol inhibition of renal prostaglandin synthesis and consequent moderation of vasopressin's action.

Effect of an acute oral ibuprofen intake on urinary aquaporin-2 excretion in healthy humans

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase and thereby block the prostaglandin (PG) synthesis in the kidneys. In animals, PG interferes with the formation of aquaporin 2 in the distal renal tubules. The purpose was to measure the effect of ibuprofen on urinary excretion of aquaporin-2 (u-AQP2), urinary output, urinary osmolality (u-osm) and plasma concentration of vasopressin (AVP) in a dose-response study using placebo and ibuprofen 600 mg and 1200 mg. In 12 healthy subjects, urine was collected in 6 periods between 07.00 h and 13.00 h, and blood samples were drawn at 60-min intervals. The study medication was given 10 h and 1 h before the study. U-AQP2 and AVP were determined by radioimmunoassays. U-AQP2 decreased 33% in the placebo group and increased 47% in the ibuprofen groups. There was a highly significant difference between the placebo group, on the one hand, and the ibuprofen groups, on the other. There was a small but significant increase in AVP in the placebo group and the 600 mg ibuprofen group, but not in the 1200 mg ibuprofen group. Urinary output was at maximum after 2 h, with a 394%, 1020% and 714% increase for placebo, 600 mg ibuprofen and 1200 mg ibuprofen, respectively. U-osm decreased during the experiment in all three groups. Inhibition of renal prostaglandin synthesis by ibuprofen affects the distal part of the nephron by increasing u-AQP2. This increase was not related to changes in AVP, urinary output or urinary osmolality. We suggest that the increased excretion of AQP2 can be explained by an increase in the ratio of AQP2 that is shed into the urine because the endocytic retrieval of AQP2 from the apical membrane is impaired. This could not be revealed by changes in the osmoregulatory system by the low doses of ibuprofen used in the present study.

Diclofenac and NS-398, a selective cyclooxygenase-2 inhibitor, decrease agonist-induced contractions of the pig isolated ureter.

Non-steroidal anti-inflammatory drugs (NSAIDs) are currently considered a first-line treatment of renal colic. Their action has been ascribed to the inhibition of renal prostaglandin synthesis, which decreases renal blood flow and diuresis, and consequently lowers the pressure in the renal pelvis and ureter. However, the effects of NSAIDs on induced contractions of ureteral smooth muscle have received little attention. Also, there is a lack of clinically relevant spasmolytic drugs for the ureter. Therefore, we studied the influence of the non-selective cyclooxygenase (COX) inhibitor diclofenac, a NSAID drug customarily used in the treatment of renal colic, and of NS-398, a selective COX-2 inhibitor, on induced contractions of the pig ureter. Serotonin (0.1-30 microM), norepinephrine (0.1-30 microM) and neurokinin A (0.03-10 microM) induced reproducible concentration-dependent contractions, which were inhibited by diclofenac and NS-398 (10-300 microM) in a concentration-dependent manner. The sensitivity of neurokinin A-induced contractions to diclofenac was 3-4 times greater than that of the amines. Depending on the concentration, inhibition ranged between 25 and 96% of the initially induced contractile activity. In the presence of inhibitors, supramaximal concentrations of agonists were unable to trigger recuperation of the initially induced contractions. Prostaglandin F2alpha did not reverse the effect of diclofenac on agonist-induced contractions. Removal of diclofenac or NS-398 from the organ baths showed that the inhibition was totally reversible. Thus, the non-selective COX inhibitor diclofenac and the selective COX-2 inhibitor NS-398 are almost equipotent in reducing agonist-induced contractions in the isolated porcine ureter. Although the clinical relevance of this spasmolytic effect remains to be demonstrated, the data suggest that patients suffering from renal colic may benefit not only from the anti-diuretic and analgesic effects of diclofenac, but also from its potential spasmolytic properties. Moreover, selective COX-2 inhibitors may have clinical potential, as they may cause fewer side effects.

Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.

The novel cyclooxygenase- (COX)-2 inhibitor celecoxib is an effective treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. Conventional treatment for these debilitating conditions routinely involves the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), which are nonspecific inhibitors of COX-1 and COX-2. Numerous studies suggest that inhibition of renal prostaglandin synthesis by NSAIDs is deleterious to kidney function, particularly in high-risk patients. As celecoxib inhibits COX-2 and spares COX-1 at therapeutic doses, we hypothesized that it may offer an improved renal safety profile in patients at risk for NSAID-induced renal toxicity. This article represents a post hoc analysis of the renal safety of celecoxib, using the safety database generated during its clinical development program. This analysis includes data from more than 50 clinical studies involving more than 13,000 subjects. Most subjects were enrolled in randomized, controlled trials (of up to 12 weeks' duration); however, more than 5000 subjects received celecoxib for as long as 2 years in a long-term, open-label study at as much as twice the maximum recommended dosage. The overall incidence of renal adverse events after celecoxib was greater than that after placebo but similar to that after NSAIDs. The most common events reported after celecoxib, namely, peripheral edema (2.1%), hypertension (0.8%), and exacerbation of preexisting hypertension (0.6%), were not time- or dose-related. Peripheral edema was not associated with increased weight or blood pressure. Furthermore, there was no evidence of drug-drug interactions between celecoxib and concomitant angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, or diuretics. We conclude that celecoxib is well tolerated by patients who may be at risk for NSAID-induced renal toxicity, such as the elderly and those with hypertension or preexisting chronic heart disease.

Aspirin renography to detect unilateral renovascular hypertension

Renal arteriography has been the gold standard for detection of renal arterial stenosis. However, it is invasive and costly and does not detect physiologic abnormalities used to differentiate incidental renal arterial stenosis from renovascular hypertension. As a noninvasive screening method for renovascular hypertension, radionuclide renograms are widely used, but their sensitivity and specificity are unsatisfactory [1–3]. For increased sensitivity and specificity in the detection of renovascular hypertension, renograms taken after the administration of captopril, an inhibitor of angiotensin converting enzyme, have been tried [1–6]. The rationale for the test is that the renin-angiotensin system is involved in the autoregulation of the glomerular filtration rate [1, 3, 4]. The tracer most suitable for this test is technetium-99m diethylenetriaminepentaacetic acid ( 99m Tc-DTPA) [2, 4, 5]. However, iodine-123-orthoiodohippu-rate ([ 123 I]OIH) is used more often for first renographic examinations, because it is excreted from the kidneys more quickly than DTPA and because it gives information about overall renal function [2]. As changes in the OIH value reflect the renal blood flow, renography with [ 123 I]OIH cannot uncover renal arterial stenosis that causes hypertension without much decreasing the renal blood flow. Prostaglandin (PG) acts as a vasodilator to maintain the renal blood flow, especially when renal artery stenosis is at the borderline for autoregulation of blood flow [7–9]. In subjects with unilateral renovascular hypertension, synthesis of PGE 2 is increased in the stenotic kidney, and the PG is important pathophysiologically in accelerating renin release [10]. Inhibition of renal PG synthesis might be useful in renography with [ 123 I]OIH, giving more sensitive detection of renal arterial stenosis that causes hypertension. Here, we studied nine patients with or without unilateral renal arterial stenosis. We tried renography done in combination with aspirin administration, and suggest that such renography may be a new noninvasive and sensitive method to detect renovascular hypertension.

Effects of Nabumetone, A New Non-Steroidal Anti-Inflammatory Drug, on Urinary Prostaglandin Excretion in Man

Nabumetone is a non-acidic pro-drug which, after absorption, is transformed by the liver into 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite responsible for its anti-inflammatory activity. The urinary concentrations of 6MNA are very low and its urinary metabolites are weak inhibitors of cyclo-oxygenase. For these reasons we hypothesized that nabumetone could spare renal cyclo-oxygenase products and, consequently, better preserve renal function unlike most other non-steroidal anti-inflammatory drugs (NSAIDs) which are known to cause an impairment of renal function, mostly related to inhibition of renal prostaglandin synthesis. We measured serum creatinine, creatinine clearance and the urinary excretion of stable prostaglandins (PG)E 2 and 6-keto-PGF 1α, as a reflection of the renal production of PGE 2 and PGI 2, respectively, in 12 arthritic patients (5 males, 7 females) with normal creatinine clearance. Measurements were performed before and after a 2-week treatment with nabumetone (1 g day -1). 6-keto-PGF 1α and PGE 2 were measured by specific radioimmunoassays (RIA) after organic solvent extraction and silicic acid column chromatography. The assay sensitivity to detect renal cyclo-oxygenase inhibition was independently verified by measuring urinary 6-keto-PGF 1α in normal subjects before and after aspirin and ibuprofen, known inhibitors of renal prostaglandins. At the end of treatment, serum levels of 6-MNA ranged between 24.5 and 122.4 mg 1 -1, within the described therapeutic range for the drug. After nabumetone, no significant differences in the urinary excretion of the two prostaglandins with respect to baseline values were observed (for 6-keto-PGF 1α from 12.3±6.0 to 12.1± 8.7ng h -1, mean±S.D.; for PGE 2 from 12.3±13.6 to 11.3±15.3 ng h -1). Also, no changes in serum creatinine or creatinine clearance were observed. These results suggest that nabumetone does not significantly impair renal prostaglandin synthesis in patients with osteoarthritis.

Factors affecting renal microvascular blood flow in rat hyperdynamic bacteremia.

To determine whether angiotensin II and alpha-adrenergic activity contribute to the mechanism of impaired renal microvascular blood flow during hyperdynamic live Escherichia coli (E. coli) bacteremia, we used in vivo video microscopy in the chronic unilateral hydronephrotic kidney of decerebrate male Sprague-Dawley rats. Intravenous infusion of E. coli caused arteriolar constriction to 83 +/- 4% of baseline (BL) in cortical radial arteries (CRA), 82 +/- 3% of BL in afferent (AFF) arterioles, and decreased flow to 54 +/- 9% of BL. Subsequent local inhibition of renal prostaglandin synthesis with mefenamate increased preglomerular arteriolar constriction to 55 +/- 6% of BL in CRA and 51 +/- 6% of BL in AFF arterioles and decreased renal microvascular blood flow to 26 +/- 8% of BL values in E. coli animals but had no effect on control animals. Subsequent local renal angiotensin II receptor blockade with saralasin acetate increased renal microvascular blood flow in E. coli animals to 64 +/- 9% of BL by dilating CRA to 78 +/- 5% of BL and AFF arterioles to 89 +/- 5% of BL. Phentolamine caused further dilation of CRA to 104 +/- 7% BL and AFF arterioles to 116 +/- 109% and increased flow to 99 +/- 8% of BL. Acetylcholine increased diameters further to 110 +/- 3% of BL in CRA and 136 +/- 12% of BL in AFF arterioles. These data indicate that in our chronic hydronephrotic kidney model during E. coli bacteremia, renal microvascular tone is due to increased angiotensin II and alpha-adrenergic activity and some other, as yet, undefined factor.

Toradol, an Nsaid Used for Renal Colic, Decreases Renal Perfusion and Ureteral Pressure in a Canine Model of Unilateral Ureteral Obstruction

Toradol is a new parenteral, nonsteroidal anti-inflammatory drug which is efficacious in treating renal colic. In the present experiments, Toradol was administered to both control dogs and dogs with unilateral ureteral obstruction. In control dogs, Toradol had no effect on RBF or GFR, despite inhibition of renal prostaglandin synthesis (measured as urinary prostaglandin release). In contrast, RBF fell acutely by 35% (p < 0.001) within 15 minutes of Toradol administration in the setting of ureteral obstruction; contralateral RBF was unaffected. Ipsilateral ureteral pressure also fell. Changes in RBF and ureteral pressure, together with the known effects of NSAIDs on pain pathways, may contribute to the pain relief observed clinically with Toradol. However, the abrupt changes in renal hemodynamics brought on by Toradol to the obstructed kidney may compromise renal reserve, and Toradol should be used cautiously in treating renal colic.

Acute Renal Failure Following Binge Drinking and Nonsteroidal Antiinflammatory Drugs

Two college students who developed reversible acute deterioration in renal function following binge drinking of beer and the use of nonsteroidal antiinflammatory drugs (NSAIDs) are reported. Both patients presented with back and flank pain with muscle tenderness, but showed no evidence of overt rhabdomyolysis. The first case had marked renal failure, with a peak serum creatinine reaching 575 mumol/L (6.5 mg/dL), and acute tubular necrosis was documented by renal biopsy. The second case had only modest elevation in serum creatinine, and renal function rapidly improved on rehydration. The contribution of the potential muscle damage associated with alcohol ingestion to the changes in renal function in these two cases is not clear. However, the major mechanism for the acute renal failure was thought to be related to inhibition of renal prostaglandin synthesis in the face of compromised renal hemodynamics secondary to alcohol-induced volume depletion.

Influence of NSAID-induced inhibition of renal prostaglandin synthesis on inorganic sulfate clearance in rats.

The objective of the present investigation was to examine the influence of inhibition of renal prostaglandin synthesis on the renal clearance of inorganic sulfate, an electrolyte involved in the biotransformation of both exogenous and endogenous substrates. Homeostasis of inorganic sulfate is maintained predominantly by renal reabsorption in the proximal tubule. Using a crossover study design, the renal clearance of sulfate was assessed in conscious female Lewis rats during control periods and following the infusion of two structurally dissimilar nonsteroidal anti-inflammatory drugs, ibuprofen (IBU) and indomethacin (INDO). Animals were infused with IBU or INDO to achieve steady state concentrations of 59 +/- 8 micrograms/ml (mean +/- SD) of IBU and 22 +/- 3 micrograms/ml of INDO. At these serum concentrations, IBU and INDO produced greater than 80% decrease in the urinary excretion of prostaglandin (PG) E2. Treatment with either IBU or INDO significantly increased the renal clearance of sulfate, but did not alter the glomerular filtration rate as assessed by creatinine clearance. The role of prostaglandins in the effects of IBU and INDO on sulfate homeostasis was investigated by examining the influence of concomitant intraarterial PGE2 administration (infusion of 0.1 micrograms/min) on nonsteroidal anti-inflammatory drug-induced alterations in sulfate renal clearance. Although PGE2 alone did not significantly alter the renal clearance of inorganic sulfate or that of creatinine, the PGE2 infusion abolished the effects of IBU on sulfate renal clearance. Concomitant PGE2 administration also significantly increased the sulfate reabsorption rate in INDO-treated animals; other parameters were not significantly changed, although the fractional reabsorption of sulfate tended to increase (P = 0.17). The reason for the less pronounced effect on PGE2 on the INDO-sulfate interaction is as yet unknown, but may be partly due to additional mechanisms involved in the INDO-induced alterations in sulfate clearance. The results of these studies suggest that prostaglandin inhibition represents one mechanism whereby IBU can alter the renal clearance of inorganic sulfate.

Effects of dietary fish oil on renal growth and function in uninephrectomized rats

The basic mechanisms of renal growth remain poorly understood. The work hypertrophy theory holds that after an acute reduction in renal mass, the growth of the kidney occurs as a consequence of increased renal function. Pharmacological inhibition of renal prostaglandin synthesis impairs the acute adaptive increases in both renal function and mass following partial nephrectomy. The present study examines the effects of four weeks of dietary fish oil on renal growth, function and arachidonic acid metabolites in intact and uninephrectomized male Sprague-Dawley rats. Dietary fish oil interferes with dienoic prostaglandin and thromboxane production in favor of synthesis of trienoic analogues. Control animals were pair-fed an identical diet with the exception that the fat was replaced by beef tallow. Renal cortical concentrations of arachidonic acid metabolites were reduced in animals fed fish oil, and urinary excretion of prostaglandin E2 was impaired. Fish oil feeding resulted in increased kidney weight without concomitant increases in renal function in intact animals. Glomerular filtration rate and renal plasma flow were greater in uninephrectomized rats fed fish oil compared to uninephrectomized controls pair-fed beef tallow. Augmentation of the compensatory increases in renal function observed with fish oil feeding was not associated with any additional renal hypertrophy. These data indicate that dietary fish oil has a profound impact on renal growth and function, which may be the consequence of altered renal and/or extrarenal arachidonic acid metabolism. Furthermore, the direction of the alterations in renal mass oppose that of renal function, providing clear and unique evidence against the work hypertrophy theory of renal growth.

Renal effects of angiotensin II: role of prostaglandins?

In the present study the possible role of endogenous prostaglandins in modulating the renal effects of angiotensin II was investigated in the isolated perfused rat kidney. Angiotensin II (5 ng/ml) caused both an increase in prostaglandin E2 synthesis and an increase in renal vascular resistance, as well as an increase in perfusate flow rate and glomerular filtration rate. Filtration fraction did not change. Inhibition of prostaglandin synthesis did not influence these effects of angiotensin II. In addition, angiotensin II caused natriuresis and to a lesser degree kaliuresis. These effects were independent of intrarenal hemodynamic effects. Inhibition of renal prostaglandin synthesis did not have any effect on the angiotensin-induced natriuresis. We conclude that the natriuretic effect of angiotensin II is independent of renal prostaglandin synthesis.

Inhibition of renal prostaglandin synthesis in man: methodological and clinical implications.

Integrity of renal prostaglandin synthesis is necessary to maintain renal cortical and medullary function in patients with kidney, heart and liver disease. A comparison of the biochemical effects of various non-steroidal anti-inflammatory drugs (NSAIDs) necessitates that renal prostaglandin synthesis, as reflected by urinary immunoreactive prostaglandin excretion, be assessed with proper attention to problems created by seminal fluid contamination, inadequate chromatographic separation of samples, and largely unknown cross reactivities of systemic eicosanoid metabolites with antibodies raised against primary prostaglandins. Most, but not all, clinical studies support the observation that conventional doses of sulindac, administered orally, do not inhibit renal prostaglandin synthesis or alter renal function. Caution is in order, however, about the use of any NSAID, including sulindac at conventional dosage, in patients with severe liver disease as the plasma levels of sulindac sulfide are increased and prolonged compared to patients with normal hepatic function. Furosemide-induced natriuresis is probably not prostaglandin-mediated, in contrast to increased in renal blood flow and renin release. Some NSAIDs can attenuate the efficacy of antihypertensive therapy. Inasmuch as sulindac does inhibit systemic vascular prostacyclin production, its lack of hypertensive effect vis-a-vis other NSAIDs argues in favor of the importance of intrarenal prostaglandin-dependent mechanisms in mediating the hemodynamic effects of non-selective cyclooxygenase inhibitors.

Antidiuresis and decreased sodium excretion during cyclo-oxygenase inhibition in the conscious dog.

Studies were undertaken to further elucidate the role of endogenous prostaglandins in normal renal function in the awake dog. Meclofenamate (2 mg/kg and 2 mg/kg/h, i.v.) was administered after control measurements. Parallel time control experiments were also performed. Inhibition of renal prostaglandin synthesis was documented by significant reduction in urinary prostaglandin E2 excretion rate. Urine flow and sodium excretion were reduced by meclofenamate infusion. In addition, fractional excretion of sodium was reduced, implying enhanced sodium reabsorption during prostaglandin synthesis inhibition. Renal hemodynamics, glomerular filtration and systemic hemodynamics were unaffected. It is concluded that endogenous prostaglandin release is important in influencing sodium and water excretion in the conscious dog.

Angiotensin-induced sodium excretion patterns in cirrhosis: Role of renal prostaglandins

Changes in renal hemodynamics and sodium excretion induced by an angiotensin II (AII) infusion were correlated with urinary prostaglandin E2 (PGE2) excretion in 15 patients with cirrhosis and ascites. All induced natriuretic responses in 47% and antinatriuretic responses in 53% of the patients. Natriuresis was accompanied by an increase; antinatriuresis by a decrease in PGE2 excretion. Although there was no change in GFR (CIn), renal blood flow (CPAH) decreased. Patients were clinically indistinguishable. Antinatriuretic responders tended, however, to have higher baseline PGE2 excretion rates, were more sensitive to effects of prostaglandin blockade, and were less sensitive to the pressor effect of AII. Following partial inhibition of renal prostaglandin synthesis by indomethacin, AII-induced natriuretic responses were accentuated. GFR, RBF, and urine flow rate markedly decreased in both groups. There was no difference in pressor sensitivity to AII following prostaglandin synthesis blockade. We conclude that in patients with hepatic cirrhosis, the sodium excretion pattern induced by an exogenous AII challenge may depend on the prior state of intrarenal prostaglandin activity. Our findings also support the hypothesis that renal hemodynamic parameters in patients with cirrhosis and ascites are crucially dependent on renal prostaglandins.

Renal prostaglandins and sodium balance in the rabbit: lack of effect of aspirin-like drugs.

Urinary prostaglandin E2 (PGE2) and PGF2 excretion was previously found to be inversely related to sodium intake in the rabbit. Renal prostaglandin (PG) synthesis might therefore be involved in the renal handling of sodium. This possibility was tested by studying sodium excretion during inhibition of renal PG synthesis with four different nonsteroidal anti-inflammatory drugs in unanaesthetized, female rabbits. The rabbits n = 5-6) were kept in metabolic cages and chronically maintained on different sodium containing diets. On a medium salt diet (0.4% NaCl), neither treatment with indomethacin (1.5 mg/kg x 2 or 3 mg/kg x 2) nor diclofenac (1.5 mg/kg x 2) for three days changed the urinary excretion of sodium and water although the mean excretion of immunoreactive PGE2 (iPGE2) and iPGF2 were reduced by between 43-78%. On a very low salt diet (0.05% NaCl), two days treatment with aspirin (30 mg/kg x 2), diclofenac (3 mg/kg x 2), indomethacin (3.5 mg/kg x 2) or naproxen (10 mg/kg x 2) did not alter sodium excretion in any significant direction. The mean urinary PGE2 and PGF2 excretion was reduced by 35-63% and 63-85%, respectively. These results do not support a major role of PGs in the chronic regulation of sodium balance in the rabbit. The possible influence of mineralocorticoids on renal PG synthesis was studied by administration of aldosterone (100 microgram/kg x 2) for two days to rabbits on a high salt diet (2% NaCl) and cancrenoate (10 mg/kg x 2), an aldosterone antagonist, to rabbits on the very low salt diet. However, neither drug significantly changed the urinary excretion of PGF2 alpha, indicating that renal PG synthesis is not influenced by mineralocorticoids in the rabbit.

Renal Actions of Oxyphenbutazone

Oxyphenbutazone decreased the renal excretion of sodium and water in anesthetized dogs. As these excretions decreased, the drug also produced a decrease in renal blood flow and in the glomerular filtration rate. Blood pressure increased slightly. These changes are consistent with an inhibition of renal prostaglandin synthesis and could explain why oxyphenbutazone is reported to produce weight gain and edema when used clinically.